This invention relates to novel hydroxamic acid and carboxylic acid derivatives which are inhibitors of matrix metalloproteinases to pharmaceutical compositions comprising such compounds and to their use in the treatment of diseases and conditions responsive to modulation of matrix metalloproteinase activity.
The matrix metalloproteinases (MMPs) are a family of enzymes including interstitial collagenase, neutrophil collagenase, collagenase-3, 72kDa gelatinase, 92kDa gelatinase, stromelysin-1, stromelysin-2, stromelysin-3, matrilysin, macrophage metalloelastase, membrane-type metalloproteinase-1 and membrane-type metalloproteinase-2. These enzymes share a common zinc-containing catalytic domain and a pro-sequence which maintains latency. A wide range of cells and tissues can express MMPs in response to activation by inflammatory stimuli such as interleukin-1 or tumour necrosis factor-xcex1 (TNF-xcex1). Different stimuli can induce overlapping yet distinct repertoires of MMPs and different cell types can respond to the same stimuli by expression of distinct combinations of MMPs. MMPs can degrade the protein components of extracellular matrix such as collagens, vitronectin and elastin, and have recently been shown to process membrane proteins such as pro-TNF-xcex1 to release soluble TNF-xcex1. MMPs are thought to play a central role in the pathology of inflammatory diseases such as rheumatoid arthritis as well as in the growth and metastasis of tumours.
Compounds which have the property of inhibiting the action of MMPs are thought to be potentially useful for the treatment or prophylaxis of conditions involving such tissue breakdown, for example rheumatoid arthritis, osteoarthritis, osteopenias such as osteoporosis, periodontitis, gingivitis, corneal epidermal venous, diabetic or gastric ulceration, ulcerative colitis, Crohn""s disease, pressure sores, and tumour metastasis, invasion and growth. MMP inhibitors are also of potential value in the treatment of neuroinflammatory disorders, including those involving myelin degradation, for example multiple sclerosis, as well as in the management of angiogenesis dependent diseases which include arthritic conditions and solid tumour growth as well as psoriasis, proliferative retinopathies, neovascular glaucoma, ocular tumours, angiofibromas and hemangiomas, cardiac and cerebral infarction, and wound healing.
A known class of collagenase inhibitors is represented by those disclosed in EP-A-0574758 (Roche), EP-A-0684240 (Roche), and WO 95/33731 (Roche). In general, the compounds disclosed in those publications may be represented by the structural formula (IA): 
in which R1, R2 and the N-containing ring are variable in accordance with the specific disclosures of the publications.
Another known class of MMP inhibitors is represented by those disclosed in EP-A-0606046 (Ciba-Geigy) WO 96/00214 (Ciba-Geigy), WO 95/35275 (British Biotech) and WO 95/35276 (British Biotech), which in general may be represented by the structural formula (IB): 
in which R1, R2 and and R3 are variable in accordance with the specific disclosures of the publications.
WO 99/24399 (Darwin Discovery Ltd), published May 20, 1999, discloses MMP inhibitors inter alia of structural formula (IC) 
wherein X is xe2x80x94SO2xe2x80x94or xe2x80x94SOxe2x80x94, and R1, R2 and each B is as defined in the document.
The present invention makes available a new class of inhibitors of MMPs which, as a result of that activity, are useful in the management of diseases or disorders associated with over production of or over responsiveness to MMPs. The compounds of the invention differ in structure from those of WO 99/24399 inter alia in that the methylene group equivalent to that marked with an asterisk in formula (IC) is substituted in the present compounds.
According to the present invention there is provided a compound of formula (I) 
wherein
X represents a carboxylic acid group xe2x80x94COOH, or a hydroxamic acid group xe2x80x94CONHOH;
R2 represents a radical of formula (II)
R3xe2x80x94(ALK)mxe2x80x94(Q)pxe2x80x94(ALK)nxe2x80x94xe2x80x83xe2x80x83(II)
xe2x80x83wherein
R3 represents hydrogen or an optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, or optionally substituted heterocyclic ring having 5 or 6 ring members,
each ALK independently represents an optionally substituted divalent C1-C3 alkylene radical,
Q represents xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94S(O2 )xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94OC(O)xe2x80x94or xe2x80x94N(R9)xe2x80x94wherein R9 is hydrogen, C1-C6alkyl, or C1-C6alkoxy, and
m, n and p are independently 0 or 1;
R1 represents a radical of formula (II) as defined for R2, except that R1 is not hydrogen;
W represents a cyclic amino radical of formula (IIIA) or (IIIB): 
xe2x80x83wherein
Y represents xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94S(O2 )xe2x80x94, xe2x80x94N(R8)xe2x80x94, or xe2x80x94(CH(R8))xe2x80x94, or xe2x80x94(Cxe2x95x90N-R8)xe2x80x94wherein R8 is a radical of formula (II) as defined in relation to R2; and
(i) R4, R5 R6 and R7 each independently represents a radical of formula (II) as defined in relation to R2, and R4a and R7a each independently represent hydrogen or C1-C3 alkyl, or
(ii) R4, R4a and R5 taken together with the carbon atoms to which they are attached form an optionally substituted benzene or pyridine ring fused to the cyclic amine ring, R7a represents hydrogen or C1-C3 alkyl, and R6 and R7 each independently represents a radical of formula (II) as defined in relation to R2, or
(iii) R4, R4a and R5 taken together with the carbon atoms to which they are attached form an optionally substituted benzene or pyridine ring fused to the cyclic amine ring, R6, R7 and R7a taken together with the carbon atoms to which they are attached also form an optionally substituted benzene or pyridine ring fused to the cyclic amine ring, or
(iv) when W is a cyclic amino radical of formula (IIIA) wherein Y is xe2x80x94(CH(R8))xe2x80x94, then R4 R4a and R8 taken together with the carbon atoms to which they are attached form an optionally substituted benzene or pyridine ring fused to the cyclic amine ring, R7a represents hydrogen or C1-C3 alkyl, and R5, R6 and R7 each independently represents a radical of formula (II) as defined in relation to R1 and R2, or
(v) when W is a cyclic amino radical of formula (IIIB) then R4, R4a, R7 and R7a taken together with the carbon atoms to which they are attached form an optionally substituted benzene or pyridine ring fused to the cyclic amine ring, and R5 and R6 each independently represents a radical of formula (II) as defined in relation to R1 and R2,
or a pharmaceutically acceptable salt, hydrate or solvate thereof.
As used herein the term xe2x80x9cC1-C3alkylxe2x80x9d means a straight or branched chain alkyl moiety having from 1 to 3 carbon atoms, including for example, methyl, ethyl and n-propyl.
As used herein the term xe2x80x9cdivalent C1-C3alkylene radicalxe2x80x9d means a saturated hydrocarbon chain having from 1 to 3 carbon atoms and two unsatisfied valencies.
As used herein the term xe2x80x9ccycloalkylxe2x80x9d means a saturated alicyclic moiety having from 3-8 carbon atoms and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
As used herein the term xe2x80x9ccycloalkenylxe2x80x9d means a saturated alicyclic moiety having from 5-8 carbon atoms and at least one double bond, and includes, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl.
As used herein the term xe2x80x9carylxe2x80x9d means a mono-, bi- or tri-cyclic carbocyclic aromatic group, and includes groups consisting of two covalently linked monocyclic carbocyclic aromatic groups. Illustrative of such groups are phenyl, biphenyl and napthyl.
As used herein, the term C3-C8 carbocyclic ring means a ring of 3 to 8 carbon atoms, with no heteroatom as part of the ring. The term includes aromatic (aryl) and non aromatic (non aryl) carbocyclic rings, for example the benzene ring and cycloalkyl rings.
As used herein the term xe2x80x9cheteroarylxe2x80x9d refers to a 5- or 6- membered aromatic ring containing one or more heteroatoms, and optionally fused to a benzyl or pyridyl ring; and to groups consisting of two covalently linked 5- or 6- membered aromatic rings each containing one or more heteroatoms; and to groups consisting of a monocyclic carbocyclic aromatic group covalently linked to a 5- or 6- membered aromatic rings containing one or more heteroatoms, Illustrative of such groups are thienyl, furyl, pyrrolyl, imidazolyl, benzimidazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, 4-([1,2,3]-thiadiazoly-4-yl)phenyl and 5-isoxazol-3-ylthienyl.
As used herein the terms xe2x80x9cheterocyclic ring having 5 or 6 ring membersxe2x80x9d xe2x80x9cheterocyclylxe2x80x9d or xe2x80x9cheterocyclicxe2x80x9d includes xe2x80x9cheteroarylxe2x80x9d as defined above, and in addition means a 5 or 6 membered aromatic or non-aromatic heterocyclic ring containing one or more heteroatoms selected from S, N and O, and optionally fused to a benzene ring, including for example, pyrrolyl, furyl, thienyl, piperidinyl, imidazolyl, oxazolyl, thiazolyl, thiadiazolyl, pyrazolyl, pyridinyl, pyrrolidinyl, pyrimidinyl, morpholinyl, piperazinyl, indolyl, benzimidazolyl, maleimido, succinimido, phthalimido and 1,3-dioxo-1,3-dihydro-isoindol-2-yl groups.
Where any group herein is referred to as xe2x80x9coptionally substitutedxe2x80x9d this means the group may be unsubstituted or substituted with at least one substituent selected from (C1-C3)alkyl, (C1-C3)alkoxy, oxo, phenyl, phenoxy, hydroxy, mercapto, (C1-C6)alkylthio, amino, halo (including fluoro, chloro, bromo and iodo), trifluoromethyl, cyano, nitro, xe2x80x94COOH, xe2x80x94CONH2, xe2x80x94COORA, xe2x80x94NHCORA, xe2x80x94CONHRA, NHRA, NRARB, or xe2x80x94CONRARB wherein RA and RB are independently (C1-C3)alkyl.
Salts of the compounds of the invention include physiologically acceptable acid addition salts for example hydrochlorides, hydrobromides, sulphates, methane sulphonates, p-toluenesulphonates, phosphates, acetates, citrates, succinates, lactates, tartrates, fumarates and maleates. Salts may also be formed with bases, for example sodium, potassium, magnesium, and calcium salts.
There are at least two actual or potential chiral centers in the compounds according to the invention because of the presence of asymmetric carbon atoms. The presence of several asymmetric carbon atoms gives rise to a number of diastereomers with R or S stereochemistry at each chiral center. The invention includes all such diastereomers and mixtures thereof.
In the compounds of the invention:
X is a carboxylic acid group xe2x80x94COOH, or a hydroxamic acid group xe2x80x94CONHOH;
R1 may be, for example, an optionally substituted C1-C6alkyl, phenyl, or phenyl(C1-C6alkyl)xe2x80x94 group;
R2 may be, for example hydrogen, or an optionally substituted C1-C6alkyl, phenyl(C1-C6alkyl)xe2x80x94 group, or an optionally substituted heterocyclic group;
W may be, for example a radical of formula (IIIC), (IIID) or (IIIE) 
xe2x80x83wherein R10 is as defined in relation to R2 in formula (I), for example an optionally substituted phenyl, biphenyl, phenyl(C1-C6alkyl)xe2x80x94, phenoxy, phenoxy(C1-C3)alkyl, or heterocyclic group;
Thus, examples of compounds of the invention include those wherein
X is a carboxylic acid group xe2x80x94COOH, or a hydroxamic acid group xe2x80x94CONHOH;
R1 is n-propyl, iso-propyl n-butyl, iso-butyl, benzyl, phenylethyl, 4-fluorobenzyl, or 4-fluorophenylethyl;
R2 is hydrogen, n-propyl, n-butyl, iso-butyl, benzyl, phenylethyl, tetrahyd ropyranyl, 1-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)propyl, or 1-(phthalimido)-propyl;
W is a radical of formula (IIIC), (IIID), or (IIIE) wherein R10 is n-propyl, n-butyl or iso-butyl; or a phenyl, phenoxy, benzyl, phenylethyl, phenylpropyl, . phenoxy, or phenoxymethyl group, any of which may be substituted in the phenyl ring, for example in the 4-position, by chloro, fluoro, methoxy or cyano; pyridinyl or pyridinyloxy either of which may be substituted by chloro, fluoro, methoxy or cyano; or biphenyl or 4-pyridinylphenyl, either of which may be substituted in either ring by chloro, fluoro, methoxy or cyano. Examples of W radicals include 4-phenylmethylpiperidinyl, 4 methylpiperidinyl, 4-(4-methylphenyl)piperidinyl, 4-(4-chlorophenoxy)piperidinyl, 4-phenylpiperidinyl, 4(4-fluorophenyl)piperidinyl, 4-(4-fluorophenoxy)piperidinyl, 4-(4-pyridinyloxy)-piperidinyl, 4-(4-cyanophenyloxy)piperidinyl, 4-(4-cyanophenoxyimino)-piperdinyl, 4-(4xe2x80x2-chloro-biphenyl4-yl)-piperdinyl, 4-(2-chloro-biphenyl-4-yl) piperdinyl, 4-(4-fluorophenylmethyl)piperidinyl, 4-(4-fluorophenoxymethyl)-piperidinyl, 4-phenylpiperazinyl, 4-(4-fluorophenyl)piperazinyl, 4-(4-pyridinyl-methyl)piperazinyl, 4-(4-chlororophenyl)piperazinyl, 4-pyridin-4-ylpiperazinyl, 4-phenylmethylpiperazinyl, and 4-(4-fluorophenylmethyl)piperazinyl.
Specific examples of compounds in accordance with the invention include those named and characterised in the Examples herein, and pharmaceutically acceptable salts, hydrates or solvates thereof. One interesting compound of the invention is 3-[4-(4-fluoro-phenoxymethyl)-piperidine-1-sulfonyl]-N-hydroxy-4-phenyl-butyramide, and its pharmaceutically acceptable salts, hydrates and solvates. This compound is an inhibitor of collagenase-3 (MMP-13), in particular. Another interesting compound of the invention is 3-(4-benzyl-piperidine-1-sulfonyl)-N-hydroxy4-phenyl-butyramide, and its pharmaceutically acceptable salts, hydrates and solvates. This compound is an inhibitor of gelatinase A, in particular.
Compounds of the invention wherein X is a hydroxamic acid group may be prepared by a process which comprises causing a carboxylic acid of the invention of general formula (IV) 
or an activated derivative thereof to react with hydroxylamine, O-protected hydroxylamine, N,O-diprotected hydroxylamine, or a salt thereof, W, R1 and R2 being as defined in general formula (I), and subsequently removing any protecting groups from the hydroxylamine moiety Conversion of (IV) to an activated derivative such as the pentafluorophenyl, hydroxysuccinyl, or hydroxybenzotriazolyl ester may be effected by reaction with the appropriate hydroxy compound in the presence of a dehydrating agent such as dicyclohexyl dicarbodiimide (DCC), N,N-dimethylaminopropyl-Nxe2x80x2-ethyl carbodiimide (EDC), or 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ).
Examples of O-protected hydroxylamines for use in the process of the invention above include O-benzylhydroxylamine, O-4-methoxybenzylhydroxylamine, O-trimethylsilylhydroxylamine, and O-tert-butoxycarbonylhydroxylamine.
Examples of O,N-diprotected hydroxylamines for use in the process of the invention include N,O-bis(benzyl)hydroxylamine, N,O-bis(4-methoxybenzyl)hydroxylamine, N-tert-butoxycarbonyl-O-tert-butyidimethylsilylhydroxylamine, N-tert-butoxycarbonyl-O-tetrahydropyranylhydroxylamine, and N,O-bis(tert-butoxycarbonyl)hydroxylamine.
Carboxylic acids of formula (IV) may be prepared by condensation of a sulfinyl chloride of formula (V) or a sulfonyl chloride of formula (VA) 
wherein V is a carboxyl protecting group and R1 and R2 are as defined with respect to formula (I), with a cyclic amine W-H wherein W is as defined with respect to formula (I) followed, in the case of the sulfinyl chloride (V), by oxidation of the sulfinyl group to a sulfonyl group and, in each case, thereafter removing the protecting group V.
Sulfinyl chlorides of formula (V) may be prepared by reaction of an acetylthio compound of formula (VI) 
wherein V is a carboxyl protecting group and R1 and R2 are as defined with respect to formula (I), with sulfuryl chloride in the presence of acetic anhydride.
Sulfonyl chlorides of formula (VA) may be prepared by reaction of an acetylthio compound of formula (VI) as defined above, with chlorine and aqueous acetic acid.
Acetylthio compounds of formula (VI) may be prepared by reaction of an xcex1xcex2-unsaturated carboxylic acid of formula (VII) 
wherein R1 and R2 are as defined with respect to formula (I), with thiolacetic acid, followed by protection of the carboxylic acid group.
The preparative Examples herein give further details of the reaction conditions for the preparation of compounds of the invention and intermediates there of.
As mentioned above, the compounds of the invention are inhibitors of matrix metalloproteinases and therefore of value in the treatment of disease states or conditions resulting from over production of, or over responsiveness to, MMPs.
Accordingly in another aspect, this invention concerns:
(i) a method of treatment of conditions in mammals, in particular in humans, resulting from over production of or over responsiveness to MMPs, which method comprises administering to the mammal an effective amount of a compound as defined with respect to formula (I) above; and
(ii) a compound as defined with respect to formula (I) for use in human or veterinary medicine treatment of conditions resulting from over production of or over responsiveness to MMPs; and
(iii) the use of a compound as defined with respect to formula (I) in the preparation of an agent for treatment of conditions in mammals, in particular in humans, resulting from over production of or over responsiveness to MMPs.
Conditions resulting from over production of or over responsiveness to MMPs include rheumatoid arthritis, osteoarthritis, osteopenias such as osteoporosis, periodontitis, gingivitis, corneal. Epidermal, venous, diabetic or gastric ulceration, ulcerative colitis, Crohn""s disease, pressure sores, tumour metastasis, invasion and growth, multiple sclerosis, angiogenesis dependent diseases, which include arthritic conditions and solid tumour growth as well as psoriasis, proliferative retinopathies, neovascular glaucoma, ocular tumours, angiofibromas and hemangiomas.
According to a further aspect of the invention there is provided a pharmaceutical or veterinary formulation comprising a compound of general formula (I) and a pharmaceutically and/or veterinarily acceptable carrier. One or more compounds of general formula (I) may be present in association with one or more non-toxic pharmaceutically and/or veterinarily acceptable carriers and/or diluents and/or adjuvants and if desired other active ingredients.
Compositions with which the invention is concerned may be prepared for administration by any route consistent with the pharmacokinetic properties of the active ingredient(s).
Orally administrable compositions may be in the form of tablets, capsules, powders, granules, lozenges, liquid or gel preparations, such as oral, topical, or sterile parenteral solutions or suspensions. Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinyl-pyrrolidone; fillers for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricant, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants for example potato starch, or acceptable wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.
For topical application to the skin, the active ingredient(s) may be made up into a cream, lotion or ointment. Cream or ointment formulations which may be used for the drug are conventional formulations well known in the art, for example as described in standard textbooks of pharmaceutics such as the British Pharmacopoeia.
For treatment of the respiratory tract, the active ingredient(s) may be made up as inhaleable aerosols or sprays in which the compound is dissolved or suspended, or as inhaleable powders, by conventional formulation methods.
The active ingredient(s) may also be administered parenterally in a sterile medium. Depending on the vehicle and concentration used, the drug can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle.
Safe and effective dosages for different classes of patient and for different disease states will be determined by clinical trial as is required in the art. It will be understood that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
The following Examples illustrate embodiments of the invention. The starting xcex1,xcex2-unsaturated acids are either commercially available or may be prepared by known literature methods. In the Examples, the following abbreviations have been used:
DCM Dichloromethane
DMAP 4-Dimethylaminopyridine
DMF N,N-Dimethylformamide
EDC N-Ethyl-N1-(3-dimethylaminopropyl) carbodiimide hydrochloride
EtOAc Ethylacetate
EtOH Ethanol
HOBt 1-Hydroxybenzotriazole
MeOH Methanol
NalO4 Sodium periodate
NaOH Sodium hydroxide
NMM N-Methyl morpholine
Ph3PO Triphenyl phospine oxide
RuCl3.xH2O Ruthenium (Ill) chloride hydrate
TEA Triethylamine
TFA Trifluoroacetic acid
TLC Thin layer chromatography
1H and 13C NMR spectra were recorded using either a Bruker DPX250 spectrometer at 250.1 and 62.9 MHz respectively, or a Bruker AMX2 500 spectrometer at 500.1 and 125.7 MHz respectively. Mass spectra were obtained on a PE-SCIEX API 165 with a turbo ion spray interface. Infra red spectra were obtained on a Perkin Elmer 1600 series FTIR machine. All organic solutions were dried over MgSO4.